SN-38 glucuronidation

Fig. 12.2. Comparison of ATP-dependent transport activity between rats and humans determined in isolated bile canalicular membrane vesicles. Key 1, SN-38 glucuronide (carboxylate) 2, SN-38 glucuronide (lactone) 3, E3040 (6-hydroxy-5,7-dimethyl-2-methyl-amino-4-(3-pyridylmethyl) benzothiazole) glucuronide 4, 170 estradiol-170-D-glucuro-nide 5, grepafloxacin glucuronide 6, leuko-...

SN-38 glucuronidation is catalyzed by the polymorphic UDP-glucuronosyltransfer-ase 1A1 (UGT1A1) enzyme, which is responsible for bilirubin glucuronidation... 

UGTIAI has an important role in the metabolism of irinotecan, etoposide, epiru-bicine, and tipifamib. Irinotecan is a camptothecin derivative used in the treatment of metastatic colon cancer. Irinotecan is a prodrug since it is activated to Ethyl-10-hydroxycamptothecin (SN-38) by carboxyl esterase to exert its antitumor activity mediated by the inhibition of topoisomerase I. SN-38 undergoes UGTIAI-catalyzed glucuronide conjugation to form the inactive SN-38 glucuronide (SN-38G). 

A full characterization of the metabolic pathways of CPT-11 in human cancer patients has not been undertaken. The incomplete recovery of the irinotecan dose based on urine and bile determinations of irinotecan, SN-38, and SN-38 glucuronide suggests the presence of additional unidentified metabolites. Recently, a major metabolite, 7-ethyl-10-[4-A-(5-aminopenatoic acid)-l-piperidino]carbonyloxycamptothecin, has been identified in dogs and humans, suggesting the presence of an additional metabolic pathway (18). Renal clearance has not been reported to be a major route of elimination for these compounds in humans. 

Araki K, Fujita K, Ando Y et al. Pharmacogenetic impact of polymorphisms in the coding region of the UGTIA 1 gene on SN-38 glucuronidation in Japanese patients with cancer. Cancer Sci 2006 97 1255-1259. 

Irinotecan is an analogue of camptothecin, a topoisomerase I inhibitor that is used for the treatment of advanced colorectal cancer and a few other solid tumors. Irinotecan is first converted to an active metabolite, SN-38, which is further conjugated into the inactive SN-38 glucuronide (SN-38 G), mainly by UGTIAI, and then eliminated via the bile. A common dinucleotide (TA) repeat polymorphism (containing 5, 6, 7, or 8 copies of TA repeat) has been identified in the UGTIAI promoter TATA box. 

Table 4 Kinetic Constants for SN-38 Glucuronidation of Wild-type UGT1A9 Vs. 256N Variant...

The SN-38 glucuronide can be deconjugated in the gut to active SN-38 by bacterial glucuronidases. This entero-hepatic circulation of SN-38 results in a further plasma peak, and SN-38 released within the gut lumen has been... 

Further drug interactions occur if constitutive SN-38 glucuronidation capacity is modified. For example, phe-nobarbital may induce UGT lA activity, whereas valproic acid may inhibit it. Thus, co-administration can alter the clearance of irinotecan. 

There is increasing evidence that the extent and severity of gastrointestinal toxicity correlates with concentrations of the active compound SN-38 in the plasma and bowel. The role of plasma pharmacokinetics in predicting the severity of irinotecan-induced diarrhea has been highlighted by the introduction of a biliary index, which is the product of the relative area ratio of SN-38 to SN-38 glucuronide and the total AUC. According to preUminary evidence, preventive measures should be considered when the biliary index exceeds 3.484 hours.micrograms/ ml (107,108). 

Because SN-38 glucuronide undergoes deconjugation by bacteria-derived beta-glucuronidase in the bowel after biliary excretion, a strategy for reducing irinotecan-induced subacute diarrhea has been proposed inhibition of intestinal microflora by a broad-spectrum antibiotic. In one study, this ameliorated subacute diarrhea in subsequent cycles in six of seven patients, the prophylactic oral use of neomycin resulted in less severe forms of diarrhea compared with controls (43). About 30% of irinotecan is excreted via the bile unchanged and may be directly converted to SN-38 in the bowel by intestinal carboxyesterases however, specific nonabsorbable inhibitors of intestinal carboxyesterases for oral use are not yet available. 

A Kurita, N Kaneda. HPLC method for the simultaneous determination of the camptothetin derivative irinotecan hydrochloride, CPT-11, and its metabolites SN-38 and SN-38 glucuronide in rat plasma with a fully automated on-line solid-phase extraction system. J Chromatogr 724 335—344,1999. 

Kurita, A. Kaneda, N. High-Performance Liquid Chromatographic Method for the Simultaneous Determination of the Camptothecin Derivahve Irinotecan Hydi ochloride, CPT-11, and Its Metabolites SN-38 and SN-38 Glucuronide in Rat Plasma, J. Chromatogr. B 724(2), 335-344 (1999). 

Key Words UDP-glucuronosyltransferase lAl single-nucleotide polymorphism adverse drug reactions SN-38 glucuronidation kinetic analysis. 

Standards a stock solution (2.5 mM) of SN-38 glucuronide (kindly supplied by Yakult Honsha Co. Ltd.) is dissolved in 5 mL of methanol. A working solution (0.5-250 iiM) for calibration curves is prepared by the serial dilution of the 2.5 mM stock solution with high-performance liquid chromatography (HPLC) elution buffer. 

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